TGR5 reduces macrophage migration through mTOR-induced C/EBPβ differential translation
Alessia Perino, … , Roberto Pellicciari, Kristina Schoonjans
Alessia Perino, … , Roberto Pellicciari, Kristina Schoonjans
Published November 3, 2014
Citation Information: J Clin Invest. 2014;124(12):5424-5436. https://doi.org/10.1172/JCI76289.
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Research Article Immunology

TGR5 reduces macrophage migration through mTOR-induced C/EBPβ differential translation

Abstract

The bile acid–responsive G protein–coupled receptor TGR5 is involved in several metabolic processes, and recent studies suggest that TGR5 activation may promote pathways that are protective against diet-induced diabetes. Here, we investigated the role of macrophage-specific TGR5 signaling in protecting adipose tissue from inflammation and associated insulin resistance. Examination of adipose tissue from obese mice lacking macrophage Tgr5 revealed enhanced inflammation, increased chemokine expression, and higher macrophage numbers compared with control obese animals. Moreover, macrophage-specific deletion of Tgr5 exacerbated insulin resistance in obese animals. Conversely, pharmacological activation of TGR5 markedly decreased LPS-induced chemokine expression in primary macrophages. This reduction was mediated by AKT-dependent activation of mTOR complex 1, which in turn induced the differential translation of the dominant-negative C/EBPβ isoform, liver inhibitory protein (LIP). Overall, these studies reveal a signaling pathway downstream of TGR5 that modulates chemokine expression in response to high-fat diet and suggest that targeting this pathway has the potential to be therapeutically exploited for prevention of chronic inflammatory diseases and type 2 diabetes mellitus.

Authors

Alessia Perino, Thijs Willem Hendrik Pols, Mitsunori Nomura, Sokrates Stein, Roberto Pellicciari, Kristina Schoonjans

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Figure 6

Loss of TGR5 induces chemokine expression and macrophage migration.

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Loss of TGR5 induces chemokine expression and macrophage migration. (A a...
(A and B) mRNA levels of chemokines and their cognate receptors in eWAT of HFD-fed Tgr5bm+/+ and Tgr5bm–/– mice. n = 12 per group. (C and D) mRNA levels of chemokines and their cognate receptors in eWAT of HFD-fed Tgr5fl/fl and LysM-Cre Tgr5fl/fl mice. n = 12 per group. (E) Migration of primary macrophages isolated from Tgr5+/+ or Tgr5–/– mice in a Transwell migration assay in response to CCL2 (100 ng/ml) in the presence or absence of INT-777 (30 μM). n = 3 per group. (F) Macrophage invasion into Matrigel plugs in Tgr5+/+ and Tgr5–/– mice. Left: Quantification of macrophages that invaded the Matrigel plugs. n = 3 per group. Right: Representative MAC3 staining to detect macrophages. Original magnification, ×20. (G–I) mRNA levels of chemokines (G) Ccl2, (H) Ccl3, and (I) Ccl4 in primary BMDMs isolated from Tgr5+/+ or Tgr5–/– mice and then stimulated with LPS (10 ng/ml) for 24 hours, in the presence or absence of INT-777 (30 μM). n = 6 per group. Results represent mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001 vs. genotype; #P < 0.001 vs. control, 2-tailed Student’s t test or 1-way ANOVA with Bonferroni post-hoc analysis as appropriate.